The present invention relates to the
this of implantable vascular prosthetic devices and, more particularly, 07/695,107, a subcutaneous implant for integration into the vascular/capillary system of a patient for purposes of selectable dispensing, over an extended period of time, of pharmacologic and other bio-acting agents.
A problem which has developed in contemporary pharmacology and areas of bioengineering is that many bio-acting molecules resultant from these efforts are of a size, length, weight or complexity such that they are subject to attack by enzymatic processes within the digestive tract when such drugs or bio-engineered agents are taken enternally (orally). Further, the state-of-the-art of encapsulation and matrixing of drugs to minimize the effect of digestive tract acids, and to extend the release periods thereof, are generally limited to a number of hours in the resultant effective time period of release of such agents.
Recognizing the above limitations of orally delivered bio-acting agents, and realizing the limitations of drug delivery by means of hypodermic injection, a number of approaches, by way of implantable micro-infusion pumps/dispensers, have appeared in the art. More particularly, such micro-pump and micro-dispensing systems have included electro-chemical means, piezo-electric means, osmotic means of both an active and passive nature, and miniaturized classical electro-mechanical delivery means. All of these technologies have, as their goal, the provision of extended time-release of drugs and other bio-active substances directly into the bloodstream of the patient. For example, U.S. Pat. No. 4,886,514 and U.S. Pat. No. 4,902,278 to Maget relate to implantable, electrochemically driven drug dispensers capable of achieving dispensing rates in the range of 0.01 ml per hour to as low as 0.001 ml (one microliter) per hour.
Implantable piezo-electric systems intended for long-term dispensing of bio-acting agents are represented by U.S. Pat. No. 4,938,742 to Sinits and U.S. Pat. No. 4,944,659 to Labbe. These technologies are entirely solid state and, therefore, are in principle capable of unlimited miniaturization and control thereof by purely electronic means. Thereby, long term, low quantity delivery systems should be achievable by these means.
The category of so-called active osmotic pumps is represented by U.S. Pat. No. 4,898,582 to Faste and U.S. Pat. No. 5,030,216 to Theeuwes which employs chemo-mechanical processes which do not require any source of electrical energy such as a battery. In this technology, a membrane is reciprocated responsive to a chemical reaction to, over extended periods of time, provide controlled, long-term release of bio-acting substances.
So-called passive osmotic pump systems have appeared for use in oral systems and have been suggested for subcutaneous delivery systems. Such pumps, which involve the use of lipids, are represented by U.S. Pat. No. 4,111,201 to Theeuwes; U.S. Pat. No. 4,439,196 to Higuchi; and U.S. Pat. No. 4,685,918 to Amidon et al. Passive osmotic pumps make use of a rigid enclosure having an expandable compartment which supplies pressure against an adjacent second compartment to effect a pressure gradient against the wall of the second compartment so that, over a prolonged period of time, a bio-acting agent within the second compartment will be forced across an aperture in the rigid enclosure and into the bloodstream or tissue of the patient. Such systems of osmotic delivery address drug delivery rates of picoliters per hour, that is, billionths of liters per hour. Accordingly, extremely low quantity and prolonged delivery rates are apparently achievable through the use of such osmotic systems. Nonetheless, these approaches do not address the needs of the patient or user having, as is often the case, the requirement for a timed, sequenced and/or pulsed delivery of a number of different bio-acting agents (often known as biologic response modifiers). Also, little is known regarding the long term effect of osmotic systems, when such systems are used in subcutaneous implants, as opposed to an orally-taken capsule.
A further concern in the area of implantable delivery systems is the ability of the vascular system to provide sufficient volume, rate, and pressure of blood flow to the delivery means to enable the bio-acting agents to enter the bloodstream on a reliable basis. Two approaches to this problem have appeared in the art. One is the approach of Powell (see U.S. Pat. No. 4,929,442) of providing an improved physiological carrier to permit the particular bio-acting agent to become more effectively transferred to the bloodstream. A second approach to the problem of access to the vascular system is reflected in U.S. Pat. No. 4,820,626 (1989) to Williams et al, which is concerned with methods of treating the surface of subcutaneous implants with microvascular endothelial cells to integrate the implant into the vascular system of the patient to achieve better bloodflow for the dispensed agents.
The instant invention is an improvement of the technology of Williams in that use is made of one or a combination of so-called vascular growth factors which communicate directly with the so-called angiogenesis gene which, it is believed, is the basis of all human vascular development. Accordingly, through the use of growth factors and related biological molecules which have been recently discovered, vascular growth of capillaries, veins and the like into the surface of an implant can be stimulated. This has been demonstrated by Ogawa, et al, "Transforming Growth Factors," 3 Growth Factors 53-62 (1990) and others, who have placed a vascular growth factor within a passive osmotic pump capsule, subcutaneously implanted the same, and thereby stimulated the growth of capillaries and related vascular structures which are identified with vascular growth and development.
Also there has appeared in the art such materials as polytetrafluoroethylene having specially configured fibers, fibrils and other structures adapted for vascular implantation. Accordingly, a combination of synthetic and organic materials have appeared in recent years which, in one fashion or another, stimulate vascular growth and/or activity.
The instant invention builds upon the above advances in molecular biology, material science and micromechanics. It more particularly provides for a selectably detachable component of a dispensing system in which a permanently implanted vascular portion of the system cooperates with the replaceable component thereof within which various biologic response modifiers and other agents may be provided and dispensed at low rates, or pulsed, over prolonged periods into the implanted vascular portion and therefrom into the human body.